Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/22—Tin compounds
  • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
• • C07F7/2212—
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
  • B01J31/22—Organic complexes
  • B01J31/2282—Unsaturated compounds used as ligands
  • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
  • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
  • C07F15/0046—Ruthenium compounds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/32—Addition reactions to C=C or C-C triple bonds
  • B01J2231/323—Hydrometalation, e.g. bor-, alumin-, silyl-, zirconation or analoguous reactions like carbometalation, hydrocarbation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
  • B01J2531/82—Metals of the platinum group
  • B01J2531/821—Ruthenium

Definitions

• the present invention refers to a process for the ruthenium catalyzed trans-selective hydrostannation of alkynes and the so-obtained products.
• alkenyltin reagents alkenylstannanes
• the Stille cross coupling reaction is arguably the most important application of organotin reagents in general and alkenyltin reagents in particular (V. Farina, V.
• alkenyltin reagents involve, but are not limited to, metal-for-tin exchange, in particular lithium-for-tin exchange, as well as halogen-for-tin exchange reactions.
• Tin hydrides can be added to alkynes under conditions involving the formation of free radicals as the reactive intermediates.
• the addition reactions are usually carried out at elevated temperatures in the presence of radical initiators such as azoisobutyronitrile (AIBN) or under ultrasonication.
• AIBN azoisobutyronitrile
• alkynes usually afford E/Z-mixtures of the corresponding alkenylstannanes (J. A. Marshall in: Organometallics in Synthesis (M. Schlosser, Ed.), Wiley, Chichester, 2002, 2 nd Ed., p. 353).
• the product ratio can change with time as the tin radicals involved in the reactions can lead to secondary isomerization of the kinetic products initially formed.
• Radical hydrostannation reactions are usually not applicable to substrates that contain other sites of unsaturation (alkenes, allenes) in addition to the alkyne, or that contain other functional groups that will react with intermediate tin radicals (halides, azides, thioethers, thiocarbamates etc).
• tin hydrides can be added to alkynes in the presence of metal catalysts (N. D. Smith, J. Mancuso, M. Lautens, Chem. Rev. 2000, 100, 3257).
• metal catalysts Na. D. Smith, J. Mancuso, M. Lautens, Chem. Rev. 2000, 100, 3257.
• palladium, nickel, rhodium and molybdenum being most commonly used.
• Such additions usually occur by suprafacial delivery of hydrogen and tin to the same ⁇ -face of a given starting material (cis-addition mode), thus furnishing the E-isomer of the resulting alkenylstannane.
• catalytic cycles based on oxidative addition of the catalyst into the Sn—H bond, hydrometalation of the alkyne substrate, followed by reductive elimination are generally proposed.
• the inventors of the present invention found the first broadly applicable, functional group tolerant and highly stereoselective ruthenium catalyzed trans-hydrostannation of alkynes. Previous ruthenium catalyzed hydrostannations of terminal alkynes were shown to deliver product mixtures containing different regio- as well as stereoisomers that are of little preparative use (K. Kikukawa et al., Chem. Lett. 1988, 881). In contrast, the present invention is directed to a process for highly stereoselective trans-hydrostannation of alkynes comprising the steps of reacting an alkyne of the formula I
• R 1 and R 2 may be the same or different and may each be selected from:
• R 1 and R 2 may be the same or different and may each be selected from straight chain or branched chain aliphatic hydrocarbons having 1 to 20 carbon atoms optionally including heteroatoms and/or aromatic hydrocarbons in the chain or aromatic hydrocarbons having 5 to 20 carbon atoms, optionally having one or more substituents selected from C 1 -C 20 -alkyl, C 5 -C 8 -heterocycloalkyl or C 6 to C 20 aromatic hydrocarbon, C 5 to C 20 heteroaromatic hydrocarbon or aryl-(C 1 -C 6 )-alkyl, heteroaryl-(C 1 -C 6 )-alkyl, or heteroatoms, or
• R 1 and R 2 together form an aliphatic hydrocarbon chain structure having 8 to 20 carbon atoms, optionally including heteroatoms and/or aromatic hydrocarbons in the chain and/or optionally having one or more substituents selected from C 1 -C 20 -alkyl, C 5 -C 8 -heterocycloalkyl or C 6 to C 20 aromatic hydrocarbon, C 5 to C 20 heteroaromatic hydrocarbon or aryl-(C 1 -C 6 )-alkyl, heteroaryl-(C 1 -C 6 )-alkyl, said chain structure optionally being substituted by one or more substituents selected from heterosubstituents, straight chain, branched chain, cyclic aliphatic C 1 to C 20 hydrocarbons, C 6 to C 20 aromatic hydrocarbon, C 5 to C 20 heteroaromatic hydrocarbon, aryl-(C 1 -C 6 )-alkyl, or heteroaryl-(C 1 -C 6 )-alkyl, or one of R 1 and
• R 1 and R 2 should preferably have a lower affinity to the Ru-central atom in the ruthenium complex than the alkyne moiety in order to avoid blocking of the reactive site thereof.
• the substituents X 1 , X 2 and X 3 in the tin hydride of the formula X 1 X 2 X 3 SnH may be the same or different and may each be selected from hydrogen, straight chain, branched chain or cyclic aliphatic hydrocarbons, preferably having 1 to 20, preferably 1 to 16 carbon atoms, or aromatic hydrocarbons preferably having 6 to 22, preferably 6 to 14 carbon atoms, or two of X 1 X 2 and X 3 together form an aliphatic hydrocarbon chain having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms in the chain, including said aliphatic hydrocarbons being bound to Sn via oxygen (such as alkoxy), said aliphatic hydrocarbon group optionally including heteroatoms in the chain and/or optionally having one or more substituents selected from C 1 -C 20 -alkyl, C 5 -C 8 -heterocycloalkyl or C 6 to C 20 aromatic hydrocarbon, C 1 to C 20 heteroaro
• the tin hydride of the formula X 1 X 2 X 3 SnH is represented by the formula in which X 1 , X 2 and X 3 may be the same or different and may each be selected from straight chain, branched chain or cyclic C 1 to C 10 aliphatic hydrocarbons each optionally being substituted by methyl, ethyl, propyl, butyl or isomers thereof, or one or more fluorine atoms.
• the higher isotopomers of the tin hydride reagents of the general formula X 1 X 2 X 3 SnH are used, in particular the corresponding tin deuterides of the general formula X 1 X 2 X 3 SnD, wherein the substituents X 1 , X 2 and X 3 can be chosen as defined above.
• the catalyst used in the inventive process is a cyclopentadienyl-coordinated ruthenium complex containing the following substructure:
• R cp1 to R cp5 may be the same or different and may each be selected from hydrogen or from straight chain, branched chain or cyclic aliphatic hydrocarbons, preferably having 1 to 20 carbon atoms, optionally including heteroatoms and/or aromatic hydrocarbons in the chain and/or optionally having one or more substituents selected from C 1 -C 20 -alkyl, heterocycloalkyl, C 6 to C 20 aromatic hydrocarbon, C 5 to C 20 heteroaromatic hydrocarbon or aryl-(C 1 -C 6 )-alkyl, heteroaryl-(C 1 -C 6 )-alkyl or heteroatoms and wherein further ligands are coordinated to the central atom ruthenium.
• the solvent used in the inventive process should be a low donor solvent and may be selected from aliphatic, cycloaliphatic solvents, fluorinated hydrocarbons, esters, ethers, ketones or mixtures thereof which may be substituted by one or more heteroatoms such as pentane, hexane, CHCl 3 , CH 2 Cl 2 , 1,2-dichloroethane, CH 3 CN, ethyl acetate, acetone, THF, diethyl ether or methyl tert-butyl ether, 1,2-dimethoxyethane (glyme), bis(2-methoxyethyl)ether (diglyme), benzotrifluoride, as long as they are not detrimental to the catalysed reaction.
• aliphatic, cycloaliphatic solvents, fluorinated hydrocarbons, esters, ethers, ketones or mixtures thereof which may be substituted by one or more heteroatoms such as pentane, hexan
• the catalyst is generally used in a molar ratio of 0.1 to 10 mol-%, preferably 1 to 5 mol-% referred to the alkyne of the general formula (I).
• the inventive process can be carried out in a temperature range from ⁇ 78° C. to 100° C., preferably at ambient temperature of between 0° and 30° C., and it proceeds at normal pressure already. If needed, the reaction can be carried out in a protective atmosphere such as nitrogen or argon.
• a heterosubstituent as defined according to the invention can be selected from —O—, ⁇ O, F, Cl, Br, I, CN, NO 2 , a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF 3 ) 2 , SF 5 , amine bound through N atom, —O-alkyl (alkoxy), —O-aryl, —O—SiR S 3 , S—R S , S(O)—R S , S(O) 2 —R S , CO 2 —R S , amide, bound through C or N atom, formyl group, C(O)—R S .
• R S 3 may be, independently from each other, the same or different and may be each an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups.
• the heterosubstituent is selected from ⁇ O, F, Cl, Br, I, CN, NO 2 , a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF 3 ) 2 , SF 5 , amine bound through N atom, —O-alkyl (alkoxy), —O-aryl.
• C 1 -C 20 -alkyl can be straight chain or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
• Alkyl might be lower alkyl such as C 1 -C 5 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewise pentyl, 1-, 2- or 3-methylpropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.
• Cycloalkyl might preferably be C 3 -C 10 -alkyl and may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Alkenyl might be C 2 -C 20 alkenyl.
• Alkynyl might be C 2 -C 20 alkynyl.
• Halogen is F, Cl, Br or I.
• Alkoxy is preferably C 2 -C 10 alkoxy such as methoxy, ethoxy, propoxy, iso-propoxy, tert-butoxy etc.
• Heterocycloalkyl having one or more heteroatoms selected from among N, O and S is preferably 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1
• Optionally substituted means unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted for each hydrogen on the hydrocarbon.
• Including heteroatoms and/or aromatic hydrocarbons in the chain means that one or more carbon atoms in the chain might be replaced by heteroatoms such as N, O or S or part of an aromatic ring structure.
• Aryl might be phenyl, naphthyl, biphenyl, anthracenyl, and other polycondensed aromatic systems.
• Aryl-(C 1 -C 6 )-alkyl might be benzyl or substituted benzyl.
• Heteroaryl having one or more heteroatoms selected from among N, O and S is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, also preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3-
• the inventors have carried out an initial screening of catalysts and solvents using tributyltin hydride as the reagent for the trans-hydrostannation of alkynes. The results are indicated in the following Table 1.
• the current procedure is also applicable to terminal alkynes as well as to alkynes bearing a heteroelement directly bound to the triple bond; the heteroelements that can be directly bound to the triple bond include silicon and halogen, which are of particular preparative relevance; in these cases, the resulting alkenyltin derivatives are usually formed with excellent regioselectivities.
• the hydrostannation of methyl 5-hexynoate as a prototype terminal alkyne substrate led to the alkenylstannane as the largely major isomer, in which the tin residue is bound to the non-terminal carbon atom (Table 2, entry 21).
• a variety of functional groups in the reaction system is tolerated, including ethers, esters, silyl ethers, sulfonates, ketones, phthalimides, azides, amides, Weinreb amides, carbamates, sulfonamides, alkenes, halides, a free carboxylic acid, unprotected hydroxyl groups as well as different heterocycles.
• This functional group tolerance further corroborates that the observed trans-hydrostannation is not the result of a radical process, since azides or halides are incompatible with tin radicals.
• the inventors assume that binding of an alkyne to the electrophilic metal center of C subsequently favors coordination of the tin hydride rather than of a second alkyne on electronic grounds.
• the acetylene moiety is supposed to function as a four-electron donor, which explains why alkenes do not react under the chosen conditions.
• This bonding situation facilitates an inner-sphere nucleophilic delivery of the hydride with formation of a metallacyclopropene F ( ⁇ 2 -vinyl complex) without prior generation of a discrete Ru—H species.
• catalysts can impart high levels of regioselectivity on the trans-hydrostannation of unsymmetrical alkynes.
• This effect of matching substrate and catalyst is broadly applicable. Further representative examples are shown in Table 3. Excellent results are usually obtained when substrates containing an acidic or slightly acidic proton in proximity to the triple bond are reacted with the appropriate tin hydride in the presence of a Cp*Ru-catalyst containing a chloride substituent.
• Preferred catalysts are [Cp*Ru(cod)Cl] (5), [Cp*RuCl 2 ] n (7), or [(Cp*RuCl) 4 ] (8) (prepared according to: P. J. Fagan et al., Organometallics 1990, 9, 1843). This strong directing effect might stem from a pre-orientation of substrate and/or tin hydride within the coordination sphere of the catalyst and/or from a change in mechanism.
• amides and sulfonamides at a propargylic (entry 14) or homopropargylic position exert a strong directing effect in the presence of a chloride-containing ruthenium catalyst such as 7 or 8.
• entries 31-34 even suggest that the level of regioselectivity is directly correlated with the acidity of —NH group of the amide or sulfonamide.
• the example shown in entry 30 demonstrates that a heterocyclic ring containing a protic site is also able to exert a strong directing effect.
• the present invention is superior to the trans-hydrostannation of alkynes based on the use of catalytic or stoichiometric amounts of strong Lewis acids such as ZrCl 4 , HfCl 4 or fluorinated borane derivatives, notably with regard to the functional group tolerance as well as the user-friendliness.
• the searching of libraries of matching candidates of alkyne, ruthenium catalyst and tin hydride provides the simple means of finding the best system for a given transition Ru-catalyzed conversion. This procedure is simple and can be performed rapidly by standard laboratory techniques or, alternatively, with modern instruments which are customary in combinatorial catalysis.
• the resulting trans-hydrostannation opens a practical new gateway to Z-configured alkenyltin derivatives which could previously only be made by indirect routes or by radical processes, which however often lead to mixtures of isomers or to different regioisomers.
• the inventors expect this stereo-complementary methodology to add another dimension to the uniquely prolific field of organotin chemistry.
• the inventive alkenyltin derivatives can be used for further synthesis of, for example, drug compounds or drug candidates, natural products, fine chemicals, agrochemicals, polymers, liquid crystals, fragrances, flavors, cosmetic ingredients, sun protective agents. Furthermore, they can be used for the preparation of compound libraries by combinatorial or parallel synthesis.
• the invention is further illustrated by the general method for trans-hydrostannation as shown in Example 1 and further exemplified in the subsequent Examples 2 to 42 for various products of the trans-hydrostannation of alkynes.
• Tributyltin hydride (0.99 mL, 3.68 mmol, 1.05 equiv) was added dropwise under Argon over 6 min to a stirred solution of and 5-decyne (0.63 mL, 3.5 mmol, 1.0 equiv) and [Cp*Ru(CH 3 CN) 3 ]PF 6 (88.2 mg, 0.175 mmol, 0.05 equiv) in dry CH 2 Cl 2 (17.5 mL) at ambient temperature. Once the addition was complete, stirring was continued for another 15 min before the solvent was evaporated. The residue was purified by filtration through a short pad of silica using hexane as the eluent.
• the Z/E ratio (NMR) was found to be 99/1 for the ⁇ -isomer and >99/1 for the ⁇ -isomer.
• the regioisomers can be separated by flash chromatography (SiO 2 ) using hexanes/EtOAc (1/0 ⁇ 50/1 ⁇ 5/1) as the eluent.
• Tributyltin hydride (1.1 mmol, 0.30 mL, 1.1 equiv) was added dropwise over 5 min to a stirred solution of [Cp*RuCl 2 ] n (n ⁇ 2) (prepared according to: N. Oshima et al., Chem. Lett. 1984, 1161) (15.4 mg, 0.025 mmol, 0.025 equiv) and 3-pentyn-2-ol (93 ⁇ L, 1.0 mmol, 1.0 equiv) in anhydrous CH 2 Cl 2 (5.0 mL, 0.2 M) under argon. The resulting mixture was stirred for 15 min before all volatile materials were evaporated.

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